The Role of Copper and CTR1 in the Regulation of Adipose Function

铜和 CTR1 在脂肪功能调节中的作用

基本信息

批准号：
10615120
负责人：
Byung-Eun Kim
金额：
$ 38.92万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615120
关键词：
Acute Adipocytes Adipose tissue Adrenergic Agents Adrenergic Receptor Affinity Biochemical Biogenesis Biological Biology Brown Fat Candidate Disease Gene Cardiomyopathies Cell Membrane Permeability Cells Cessation of life Connective Tissue Copper Cyclic AMP Defect Diabetes Mellitus Electron Transport Endosomes Energy Metabolism Etiology Exhibits Exposure to Fluorescence Microscopy Funding Generations Genetic Goals Health Hepatolenticular Degeneration Homeostasis Hormones Hour Human Impairment Injections Ionophores Iron Knockout Mice Life Link Lipids Lipolysis Location Mediating Mediator Menkes Kinky Hair Syndrome Metabolic Metabolism Metals Methods Minerals Mitochondria Modeling Molecular Mus Mutant Strains Mice Mutation Nature Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Obesity Pathogenicity Pathology Pathway interactions Patients Physiologic Thermoregulation Predisposition Prevalence Protein Family RNA Interference Regulation Resistance Roentgen Rays Role Signal Pathway Signal Transduction Site Stimulation of Cell Proliferation Sympathetic Nervous System Testing Thermogenesis Tissues Trace Elements Transcript Transition Elements Wild Type Mouse adipocyte differentiation biophysical techniques cofactor cold stress empowerment human disease hypocupremia improved in vivo insight lipid metabolism natural hypothermia novel novel therapeutic intervention pharmacologic recruit response sensor small molecule subcutaneous trafficking transcriptome uncoupling protein 1 uptake

项目摘要

Copper (Cu) is an essential trace element and Cu imbalance is the underlying etiology of several human diseases, including Menkes disease, Wilsonʼs disease, myeloneuropathy, and cardiomyopathy. Menkes disease, caused by mutations in the ATP7A Cu transporter, leads to organismal Cu deficiency that results in connective tissue defects and severe lethal neurodegeneration. Menkes patients also exhibit hypothermia, suggesting a link between Cu metabolism and mammalian thermogenic pathways. Thermogenesis is supported by several layers of metabolism coordinately regulated in multiple tissues. The major location for heat generation is adipose tissue, which responds to hormones generated by the sympathetic nervous system. For example, noradrenaline (NE) stimulation activates β3 adrenergic receptors expressed in adipose tissue, which in turn upregulates lipolysis, mitogenesis, and uncoupling protein 1 (Ucp1), culminating in a thermogenic response. It has generally been assumed that the hypothermia observed in Menkes patients is at least partly due to Cu deficiency in adipose tissue, where inadequate levels of any metal cofactor for the electron transport chain would impair the mitochondrial activity required for heat generation. However, the underlying mechanisms linking Cu homeostasis to adaptive thermogenesis have not yet been elucidated. The current proposal seeks to clarify the nature of this connection and improve our understanding of how Cu metabolism and adipose biology intersect. We plan to use genetic, pharmacological, and cell biological methods to study parallel thermogenesis models, including adipose-specific knockout mice, and cultured primary and immortalized adipocytes. Preliminary studies have shown a unique role for Cu in adaptive thermogenesis, as mice exposed to cold or adrenergic stimulators specifically import Cu (rather than both Cu and iron) into adipose tissue and mice lacking adipose expression of the high affinity Cu importer Ctr1 are more sensitive to cold exposure than mice lacking the iron importer Tfr1. We outline three specific aims to uncover how Cu homeostasis pathways intersect with thermogenic pathways in adipose tissue, and in doing so, uncover how Cu metabolism interacts with global energy regulation: (1) Establish a role for Cu in adipose thermoregulation and systemic energy homeostasis using tissue-specific Ctr1 and Atp7a mutant mice, (2) Determine how coordinated regulation of Ctr family proteins controls Cu availability in adipocytes upon β3-AR stimulation, and (3) Uncover mechanisms for CTR1-mediated thermogenesis and adipocyte browning.

铜 (Cu) 是一种必需的微量元素，铜失衡是多种人类疾病的根本病因，包括门克斯病、威尔逊病、脊髓神经病和门克斯病，由 ATP7A 铜转运蛋白突变引起，导致机体铜缺乏。导致结缔组织缺陷和严重的致命性神经变性的门克斯患者也表现出体温过低，这表明铜代谢和哺乳动物生热途径之间的联系得到了多层代谢的支持。热量产生的主要部位是脂肪组织，它对交感神经系统产生的激素做出反应，例如，去甲肾上腺素 (NE) 刺激会激活脂肪组织中表达的 β3 肾上腺素受体，从而上调脂肪分解，有丝分裂和解偶联蛋白 1 (Ucp1)，最终导致生热反应人们普遍认为 Menkes 患者中观察到的体温过低是由于至少部分是由于脂肪组织中的铜缺乏，其中电子传递链的任何金属辅助因子水平不足都会损害产热所需的线粒体活性。然而，将铜稳态与适应性产热联系起来的潜在机制尚未阐明。目前的提案旨在阐明这种联系的本质，并提高我们对铜代谢和脂肪生物学如何交叉的理解。我们计划使用遗传、药理学和细胞生物学方法来研究并行产热模型，包括脂肪特异性模型。初步研究表明，铜在适应性产热中具有独特的作用，因为暴露于寒冷或肾上腺素刺激剂的小鼠会特异性地将铜（而不是铜和铁）导入脂肪组织，而脂肪中缺乏高亲和力铜导入蛋白 Ctr1 表达的小鼠则更加敏感。我们概述了三个具体目标，以揭示铜稳态途径与生热途径的交叉。并在此过程中揭示铜代谢如何与整体能量调节相互作用：(1) 使用组织特异性 Ctr1 和 Atp7a 突变小鼠确定铜在脂肪温度调节和全身能量稳态中的作用，(2) 确定铜如何协调Ctr 家族蛋白的调节控制 β3-AR 刺激后脂肪细胞中 Cu 的可用性，以及 (3) 揭示 CTR1 介导的产热和脂肪细胞褐变的机制。